Brachytherapy Versus Stereotactic Body Radiotherapy for Cervical Cancer Boost: A Dosimetric Comparison

Background: The standard treatment for locally advanced cervical cancer involves chemo-radiation followed by brachytherapy. However, some patients are unable to undergo brachytherapy intensification. Recent advancements in radiation technology have provided several techniques, with stereotactic body radiation therapy (SBRT) theoretically able to mimic the dose distribution of brachytherapy with a high dose gradient. Methods: We analyzed 20 high-dose-rate intra-cavity brachytherapy plans for women with cervical cancer and simulated an adjunctive stereotactic radiotherapy plan at the same doses used for brachytherapy (21 Gray [Gy] in three fractions). No planning tumoral volume (PTV) margin was added for SBRT dosimetry. We used the dose constraints for brachytherapy from the EMBRACE trial and the dose constraints for SBRT in three fractions. Dose distribution, maximum dose points on target volumes, bladder, rectum, and dose-volume histograms were compared between the two techniques. Results: The mean volume of the high-risk clinical tumoral volume (CTV) was 64 cm3, and the mean volume of the intermediate-risk CTV was 93 cm3. The mean minimum dose received by 90% of the high-risk CTV (D90 CTV HR) was 17 Gy for brachytherapy versus 8.3 Gy for SBRT. The average minimum dose received by 90% of the intermediate-risk CTV (D90 CTV IR) was 7.5 Gy for brachytherapy versus 8.9 Gy for SBRT. The mean minimum dose delivered to 2cc of the bladder was 74.6 Gy for brachytherapy versus 84.7 Gy for SBRT. The mean minimum dose delivered to 2cc of the rectum was 71.8 Gy for brachytherapy versus 74.7 Gy for SBRT. Conclusion: We confirmed the dosimetric superiority of brachytherapy over SBRT in terms of target volume coverage and organ-at-risk sparing. Therefore, pending the results of further clinical studies, no current radiotherapy technique can replace brachytherapy for cervical cancer boost after external radiotherapy.


Introduction
Cervical cancer is a common type of cancer in women, with approximately 570,000 new cases and 311,000 deaths each year worldwide [1]. The incidence of cervical cancer varies significantly by region and socioeconomic status. However, cervical cancer remains a major public health problem in many developing countries where access to human papilloma virus screening and vaccination is limited.
For cervical cancer, the current standard of care for locally advanced stages consists of concomitant chemotherapy and external pelvic radiotherapy, followed by intra-cavitary brachytherapy [2]. The standard dose of radiation therapy used to treat cervical cancer is usually in the range of 45 to 50 Gray (Gy), given in daily fractions of 1.8 to 2 Gy over a period of six weeks. Brachytherapy boost doses vary depending on the type of brachytherapy used, but are generally between 15 and 30 Gy [3,4]. Overall, the exact dose of radiation therapy will depend on a number of factors, including the stage and size of the tumor, presence of pathologic lymph nodes, as well as the patient's overall health.
However, brachytherapy is not feasible in some patients because of unfavorable anatomy, contraindications to anesthesia, comorbidities, and patient refusal for the procedure, or even lack of accessibility to brachytherapy in some countries. For patients unfit for brachytherapy, noninvasive modalities, such as modulation intensity, or stereotactic body radiotherapy (SBRT) are possible.
From a technical point of view, SBRT is a type of external beam radiation therapy that delivers high doses of radiation precisely to a tumor in a few sessions. It is often used to treat small, hard-to-reach tumors in the lungs, liver and spine. Brachytherapy, on the other hand, is a type of internal radiation therapy that involves placing a radioactive source directly into or near a tumor. This can be achieved through implants or by inserting a thin tube into the tumor. Brachytherapy is often used to treat prostate and cervical cancer, as well as some types of head and neck and breast cancer.
Theoretically, SBRT is the most likely substitute for a brachytherapy dose distribution with a sharp dose gradient. Therefore, we aimed to perform a dosimetric comparison between target volume coverage and organ risk sparing, between SBRT and brachytherapy plans, as modalities for cervical boost in locally advanced cervical cancer.

Materials And Methods
Twenty patients with histologically proven locally advanced cervical cancer, epidemiologic and tumoural characteristics detailed in Table 1, previously treated with intra-cavitary brachytherapy boost, were treated with a course of chemo-radiotherapy at 46 Gy in 23 fractions of 2 Gy, five fractions per week. All treatments were performed using the conformal technique: four fields of the box technique, in our radiotherapy center.

FIGO: International Federation of Gynaecology and Obstetrics
The brachytherapy was carried out with a Fletcher applicator. A computed tomography (CT) scan with the applicator in place was performed and merged with a magnetic resonance image (MRI) to better delineate high-and intermediate-risk volumes. The target volumes and organs at risk were delineated according to the recommendations of the EMBRACE II protocol [4].
The iso-dose for the brachytherapy plan was copied onto the simulation CT for the external beam radiotherapy, and a dosimetric plan for SBRT was performed on our treatment planning system (ARIA13; Varian Medical Systems, Palo Alto, CA, USA). No planning target volume (PTV) margin was added to the high risk (HR) and intermediate risk (IR) clinical target volume (CTV), i.e. PTV equated CTV. We prescribed three fractions of 7 Gy, administered homogeneously.
We aimed to deliver a target volume as close as possible to the high-risk anatomic CTV, while respecting risk of the dose to other organs. The doses were calculated as equivalent doses delivered in fractions of 2 Gy, such that the doses were equivalent in terms of effectiveness to the prescription dose of 85 Gy at 2 Gy per fraction, assuming an alpha/beta of 10 Gy for target volumes and 3 Gy to pelvic organs at risk. Timmerman dose constraints for three fractions of SBRT were used. The optimization constraints for the SBRT and brachytherapy plans are summarized in

Results
Comprehensive patient demographics are summarized in

Discussion
Stereotactic ablative radiotherapy consists of treating localized tumors by delivering very high doses of focused radiation. This approach has led to an impressive increase in local control in multiple disease sites, including lung, liver, prostate, and spine [6,7]. Theoretically, SBRT dose distributions can mimic the dose fall-off and heterogeneity of brachytherapy plans. SBRT might therefore be useful for patients who are unable to have invasive brachytherapy due to medical comorbidities [8,9].
Historically, multiple attempts to replace brachytherapy with conventionally fractionated radiation therapy have resulted in lower local control rates [10,11]. However, with the advent of highly conformal treatments, such as SBRT, the safety and efficacy of this approach as a boost is being readdressed [12].
For the most part, boost doses range from 15 to 30 Gy for three to five fractions, with mean local control rates of 80% and high-grade toxicity rates of 10% [13,14]. Very few reports have detailed the added margins to PTV volumes. Some have short follow-up periods. Of these, our series had the largest sample size [15].
SBRT can produce a high-quality dose distribution, even for large tumors, but the dose to other organs can be less acceptable than that with brachytherapy plans. For this reason, intra-cavitary brachytherapy (and possibly interstial brachytherapy) is still dosimetrically superior to SBRT in cervical cancer [15].
While in our series, brachytherapy is significantly more effective than SBRT in covering high-risk target volumes and is significantly more protective of the bladder and rectum, a recent review by Albuquerque et al. reported a series of 15 patients undergoing SBRT for cervical cancer boost [16]. Their published dosimetric data matches ours. For instance, the median dose to the rectum was 90.63 Gy with a 2 cc dose of 25.57 Gy, while in our plan, the mean dose to the rectum was 89 Gy, but the authors concluded anyway that for patients who are unable to undergo standard brachytherapy, and thus do not have other treatment options, SBRT is feasible, with the caveat that it would be appropriate only for select patients with modest local control at the cost of possible increased late toxicity [17]. Future studies of SBRT for cervical cancer should be directed at optimizing the volume (possibly gross tumor volume alone), dose, and fractionation for this approach.
Furthermore, a recently published review by Barret et al. considered patients with cervical cancer treated with chemoradiation plus brachytherapy boost, intensity-modulated radiation therapy (IMRT) boost, or SBRT boost. It concluded that there was no significant difference in overall survival (OS) for patients who received SBRT boost versus brachytherapy boost; only IMRT had significantly lower OS than brachytherapy. This provided additional support that SBRT might be an accurate alternative for patients who are unfit for brachytherapy boost [18][19][20].
The main limitations of this study are the small sample size, the fact that applicators are not intended to be used in SBRT treatments, and the lack of clinical analysis for local control and early-late toxicity data. Further studies with a larger population should be run, in order to assess the potential clinical gain from these radiation techniques for this particular indication.

Conclusions
For patients who are not eligible for brachytherapy because of particular conditions, other curative treatment options for cervical cancer boost may include external beam radiation therapy with modulation intensity, surgery by radical hysterectomy, or palliative treatments by chemotherapy and immunotherapy. SBRT is a highly precise and targeted form of external radiation therapy that delivers a high dose of radiation to a small specific area in one or more sessions. It can be used as an alternative for cervical cancer patients unfit for brachytherapy boost. Our data confirmed the dosimetric superiority of brachytherapy, compared with SBRT, in terms of target volume coverage and sparing of at-risk organs. Therefore, we look forward to additional clinical trials to assess the outcomes of these approaches.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Mohammed VI University of Health Sciences (UM6SS) Ethics Committe issued approval SBRT-BT15Juin2020. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.